S195: IDECABTAGENE VICLEUCEL (IDE-CEL) VS STANDARD REGIMENS IN PATIENTS WITH TRIPLE-CLASS–EXPOSED (TCE) RELAPSED AND REFRACTORY MULTIPLE MYELOMA (RRMM): A KARMMA-3 ANALYSIS IN HIGH-RISK SUBGROUPS
Authors: Krina Patel, Paula Rodríguez-Otero, Salomon Manier, Rachid Baz, Marc S. Raab, Michele Cavo, Natalie Callander, Luciano Costa, Philippe Moreau, Scott Solomon, Christine Chen, Noopur Raje, Christof Scheid, Michel Delforge, Jeremy Larsen, Thomas Pabst, Kenshi Suzuki, Anna Truppel-Hartmann, Zhihong Yang, Julia Piasecki, Jasper Felten, Andrea Caia, Mark Cook, Sergio Giralt, Maria-Victoria Mateos
Journal: HemaSphere (2023)

Background: Despite improvements in the treatment landscape of RRMM with the use of combination therapy, with immunomodulatory (IMiD®) agents, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies in front-line and early relapse, patients are becoming TCE earlier in their treatment course. Outcomes in patients with high-risk disease characteristics such as cytogenetic abnormalities, advanced-disease stage, high tumor burden, presence of extramedullary plasmacytoma (EMP), and triple-class–refractory (TCR) disease also remain poor. Ide-cel, a BCMA-directed CAR T cell therapy, significantly improved median progression-free survival (mPFS; 13.3 vs 4.4 months [mo]; HR, 0.49; P<0.0001) and overall response rates (ORR; 71 vs 42%, P<0.001) vs standard (std) regimens in the overall population of patients with TCE RRMM in KarMMa-3 (NCT03651128; Rodríguez-Otero NEJM 2023; DOI: 10.1056/NEJMoa2213614). Aims: To assess the efficacy and safety of ide-cel vs std regimens in patients with high-risk disease characteristics in KarMMa-3. Methods: In KarMMa-3, patients with RRMM who received 2–4 prior regimens, who were TCE (IMiD agent, PI, and daratumumab), and had disease refractory to the last regimen, were randomized 2:1 to receive ide-cel (target dose range: 150–450 x 106 CAR+ T cells) or a std regimen (DPd, DVd, IRd, Kd, or EPd, based on prior regimen, per investigator). Efficacy (PFS, ORR, and complete response rate [CRR]) was assessed in high-risk groups including patients with cytogenetic abnormalities (del[17p], t[4;14], or t[14;16]), R-ISS stage III disease, high tumor burden (≥50% CD138-positive plasma cells in bone marrow), EMP (soft-tissue–only and soft-tissue bone-related plasmacytomas), and TCR (refractory to ≥1 each of an IMiD agent, a PI, and an anti-CD38 antibody). Results: Baseline demographics and high-risk disease characteristics were balanced between treatment arms. Median time to progression on the last prior regimen was short in patients treated with both ide-cel vs std regimens in all high-risk subgroups: cytogenetic abnormalities (5.6 vs 6.7 mo), R-ISS stage III disease (3.9 vs 3.5 mo), high tumor burden (5.1 vs 6.2 mo), EMP (5.1 vs 5.1 mo), and TCR disease (5.6 vs 5.8 mo). At a median follow-up of 18.6 mo (range, 0.4–35.4), mPFS was longer in patients treated with ide-cel vs std regimens in all high-risk subgroups: cytogenetic abnormalities (11.9 vs 4.2 mo; HR, 0.608), R-ISS stage III disease (5.2 vs 3.0 mo; HR, 0.861), high tumor burden (11.0 vs 4.9 mo; HR, 0.595), EMP (7.2 vs 2.0 mo; HR, 0.401), and TCR disease (11.2 vs 3.5 mo; HR, 0.458; Table). ORRs were improved with ide-cel vs std regimens, regardless of the presence of high-risk disease characteristics. Similarly, CRRs were improved in patients treated with ide-cel vs std regimens in all high-risk subgroups: cytogenetic abnormalities (31.8 vs 4.9%), R-ISS stage III (16.1 vs 7.1%), high tumor burden (31.0 vs 8.8%), EMP (23.0 vs 3.1%), and TCR disease (33.5 vs 1.1%). Safety data will be presented. Summary/Conclusion: Patients treated with ide-cel had a lower risk of disease progression or death and higher odds of achieving an overall response (with higher CRRs) compared with patients who received std regimens, regardless of baseline high-risk disease. Overall, these results support use of ide-cel in patients with TCE RRMM, including patients with difficult-to-treat, high-risk disease.Keywords: Clinical trial, Multiple myeloma, High risk, CAR-T